Alagille Syndrome – Clinical Features And Diagnosis

Introduction

Other names for Alagaille syndrome include Watson-Alagille syndrome, syndromic bile duct paucity (deficiency of interlobular bile duct), and Arterio-hepatic dysplasia. It is the most prevalent familial intrahepatic cholestatic condition as well as the most common intrahepatic bile duct paucity syndrome.

Genetics                    

Autosomal dominance inheritance is present in this situation (phenotype expression may vary among age groups). The illness comes in two different forms. Ninety percent of cases are for the classic illness. Mutations in the human Jagged-1 gene, or JAG-1, which codes for a ligand for the Notch-1 protein, are the cause of it. This gene is located on the short arm of chromosome 20 (20p12).

To finish the morphogenesis of diverse structures, a notch signaling pathway is involved in cellular differentiation and cell-to-cell interaction. Deviations from this pathway can affect the liver, bile duct, cardiovascular system, bones, and eyes, among other organ systems, and result in problems of these systems.

Ten percent of patients have type 2 disease. It is caused by a mutation in the Notch-2 gene and presents with symptoms resembling those of the traditional condition.

Clinical Features

Five systems are impacted in all. The disease's primary clinical determinants, the liver and biliary tract, are the first system to become affected. The vertebral or bone involvement is the second main system to become implicated. Lastly, we have cardiac involvement or congenital heart disease. Another characteristic observed is abnormal facies.

Lastly, anomalies in the anterior chamber of the eye are involved. When the condition was first characterized, it was stated that any three of the five systems that were implicated in the histology would be diagnostic because of the scarcity of the bile duct. However, this is no longer the case.

1.  Liver and Biliary Tract

Bile duct paucity is the defining feature of this disorder. Patients with it exhibit a decrease or absence of interlobular bile ducts in the portal triad, which is made up of an artery from the hepatic arterial system, a biliary ductule, and a remnant of the portal vein.

The newborn variant, which presents with jaundice-like symptoms, has conjugated hyperbilirubinemia brought on by cholestasis. Jaundice may clear up in some people, although uncontrollably severe pruritis and cholestasis may still exist. Thus, pruritis is a more problematic complaint in older children.

2. Dysmorphic Facies  

 A face known as the triangular face look is produced by it.These kids frequently feature prominent ears, a long nose with a bulbous tip, a pointed chin, a short mandible, frontal bossing, deep-set eyes with minor hypertelorism (an expanded space between the eyes), and a drooping mouth angle.

3. Congenital Heart Disease

Peripheral pulmonary artery stenosis (PLS) is the most prevalent congenital heart disease (CHD), with pulmonary valvular stenosis and tetralogy of Fallot, ASD, VSD, COA, AS, and TAPVC following in order of prevalence.

Also Read: Reye's Syndrome: Understanding A Rare But Serious Illness

Axial Skeleton and Vertebral Defects                     

Their signature finding on an AP X-ray spine is butterfly vertebrae, which result in concavities and the failure of anterior laminae to fuse. Other defects that are occasionally observed include hemivertebrae, spina bifida occulta (spinal dysraphism), short ulna, absence of the 12th rib, and an increased risk of metabolic bone disease.

Eye

Defects in the anterior chamber are frequent. The most prevalent notable anomaly is the posterior embryotoxon. The intersection of the iris and cornea is where Schwalbe's line is located. In these patients, this line becomes noticeably thicker and positioned significantly more anteriorly.

There will be a noticeable line visible laterally on the eyeball when slit lamp microscopy, which is required for these patients, is performed. Ninety percent of the instances show it. The Axenfeld abnormality, also known as Axenfeld-Rieger syndrome, is another aberration connected to posterior embryotoxon. Peripheral iris strands in these patients adhere to the posterior embryotoxon.

To observe this anomaly, slit lamp microscopy must be performed once again. Another irregularity that is observed is optic disc drusen. The extracellular area of the optic nerve head has a calcific deposit. To find it, an ocular USG check is required. Other anomalies of the eyes include Retinitis Pigmentosa, High Myopia, Shallow Anterior Chamber, and Microcornea.

Rare Features (Minor Features)

The causes of short stature are complex. It might be connected to hypothyroidism or a nutritional shortage (cholestasis). Exocrine pancreatic insufficiency, or pancreatic insufficiency, is observed. Some people may have tubulointerstitial nephropathy, which causes alterations in the kidneys and the urine sediment.

In males, defective spermatogenesis is a variable finding that might be observed. Vasculopathy is observed in conditions when the risk of stroke and Moyamoya syndrome is elevated. Hypercholesterolemia will cause xanthomas to develop. Ataxia symptoms indicative of a vitamin E deficiency will be observed.

Diagnosis       

Previously, the diagnosis was made based on the involvement of any three of the five major systems and histological evidence of bile duct scarcity. These days, the diagnosis is made using clinical characteristics that are compatible with the major systems and mutation analysis that reveals a NOTCH-2 or JAG-1 mutation.  The two mutations result in a loss of function.

Natural History                  

Roughly 10 percent of the individuals will get cirrhosis. Poor prognostic variables that suggest the developing liver illness is  TSB (total serum bilirubin) more than 6.5 mg/dL. Conjugated bilirubin of more than 4.5 mg/dL. Total serum cholesterol of more than 520 mg/dL

A higher chance of hepatocellular carcinoma in later life, albeit this condition is extremely uncommon. The mortality rate is between 20 and 25 percent. These patients are receiving supportive care. Hepatic decompensation was the primary cause of death for these patients, followed by cardiac causes.

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Hope you found this blog helpful for your NEET SS Pediatrics Gastroenterology preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.